Acetylcysteine Composition and Uses Thereof

ABSTRACT

This invention relates to novel acetylcysteine compositions in solution, comprising acetylcysteine and which are substantially free of metal chelating agents, such as EDTA. Further, this invention relates to methods of making and using the acetylcysteine compositions. The present compositions and methods are designed to improve patient tolerance and compliance, while at the same time maintaining the stability of the pharmaceutical formulation. The compositions and methods of this invention are useful in the treatment of acetaminophen overdose, acute liver failure, various cancers, methacrylonitrile poisoning, reperfusion injury during cardio bypass surgery, and radiocontrast-induced nephropathy, and can also be used as a mucolytic agent.

FIELD OF THE INVENTION

The present invention relates to acetylcysteine compositions in solutionand their use. In certain embodiments of this invention, theacetylcysteine composition is substantially free of chelating agents,which does not significantly impact the stability of the formulation. Inother embodiments of the invention, the acetylcysteine composition issubstantially free of EDTA.

BACKGROUND OF THE INVENTION

Acetylcysteine is an antioxidant having a molecular weight of 163.2 andthe following chemical structure:

(Merck Index 13^(th) ed., n90, page 17). Acetylcysteine is marketedgenerically in the United States and worldwide, as well as under thetrade names of Acetadote®, Mucomyst®, Parvolex®, Fluimucil®, and others.It is approved for several indications including treatment ofacetaminophen overdose, as an injectable and an oral agent, and as amucolytic, as an inhalation product Acetylcysteine is also being used orinvestigated to treat other indications including liver failure, variouscancers, methacrylonitrile poisoning, reduction ofradiocontrast-induceil nephropathy, and reduction of reperfusion injuryduring cardio bypass surgery.

Acetylcysteine is not a stable molecule and is oxidized and degradedwhen in solution and exposed to air. Several U.S. patents have addressedthis problem. For example, U.S. Pat. No. 5,691,380 appears to describethe use of a topical silicone-based emulsion system to improve thestability of acetylcysteine.

Other U.S. patents appear to address the problem by using a chelatingagent to stabilize the acetylcysteine. Chelating agents, or chelators,are organic agents that bond with and thereby sequester free metal ionsfrom solution, A widely used chelator is edetic acid orethylenediaminetetraacetic acid, commonly referred to as EDTA, which hasa molecular weight of 292.24 and the following chemical structure:

(Merck Index 13^(th) ed., n3546, pages 620-621). EDTA is availablecommercially as the free acid and as various salts, for example disodiumEDTA, tetrasodium EDTA, dipotassium EDTA, and calcium disodium EDTA.

U.S. Pat. No. 5,807,894, for instance, appears to describe the use ofthe chelating agent EDTA to improve the high reactivity ofacetylcysteine in a syrup formulation, U.S. Pat. No. 6,114,387 appearsto describe the use of EDTA to stabilize acetylcysteine in a soliddosage form. Aqueous solutions of acetylcysteine on the market, such asthose under the trade names of Acetadote®, Mucomyst®, Parvolex®,Fluimucil®, also contain EDTA, in the form of the salt disodium edetate,which aids in stabilizing the pharmaceutical product.

While improving the stability of acetylcysteine formulations, chelatingagents such as EDTA can cause undesirable effects when administered tohumans or animals. Some of these undesirable effects include asignificant drop in serum calcium levels (Handbook of PharmaceuticalExcipients 226 (R Rowe at al eds., 4^(th) ed., 2003)), which may resultin fatality, hypokalemia, hypomagnesemia, hypotension, and EDTA has alsobeen shown to produce reproductive developmental toxicity in testanimals. EDTA has also been associated with dose-relatedbronchoconstriction when used as a preservative in nebulizer solutions.Id. Based on the adverse effects of EDTA, particular care should betaken when administering EDTA to patients with renal impairment, livertoxicity, tuberculosis, and impaired cardiac function. Id.

Since acetylcysteine may be used to prevent or treat a variety ofdisorders and conditions, including liver damage, the addition of achelating agent such as EDTA to an acetylcysteine pharmaceutical productis of concern. Chelating agents, while stabilizing the acetylcysteinecomposition, may also decrease the effectiveness of the composition. Inaddition, some individuals are allergic to chelating agents such thatthey cannot receive acetylcysteine compositions containing a chelatingagent or may require additional care after receiving such compositions.

It would therefore be desirable to have a stable acetylcysteine solutiondrug product that does not produce adverse effects upon administration.In certain conditions, such as the use of acetylcysteine to lessen orprevent the liver damage caused by acetaminophen overdose, removing EDTAor other chelating agents could improve efficacy by limiting anyadditional liver toxicity resulting from the chelating agent.

SUMMARY OF THE INVENTION

It has been surprisingly found that an aqueous composition containingacetylcysteine, sterilized water, and a pH-adjusting agent, is stablewithout the addition of a chelating agent. Thus, the present inventionrelates to a solution containing acetylcysteine, which is substantiallyfree of chelating agents.

The pH of the aqueous pharmaceutical composition of the invention may befrom 5 to 9, from 6 to 8, from 6.5 to 7.0, or 6.8. The pH of thecomposition may be adjusted by the addition of a pH-adjusting agent,such as sodium hydroxide.

In one embodiment of the present invention the aqueous pharmaceuticalcomposition is substantially free of chelating agents. In a furtherembodiment of the present invention, the aqueous pharmaceuticalcomposition is substantially free of EDTA, or pharmaceuticallyacceptable salts thereof.

In further embodiments of the invention, the aqueous pharmaceuticalcomposition contains less than 0.05%, less than 0.02%, or no chelatingagents. In still other embodiments of the invention, the aqueouspharmaceutical composition contains less than 0.05%, less than 0.02%, orno EDTA or pharmaceutically acceptable salts thereof.

In yet another embodiment of the invention, the aqueous pharmaceuticalcomposition consists of from 10 to 400 mg/mL acetylcysteine and anadequate amount of sodium hydroxide, dissolved in deaerated water, toachieve a final pH from 6 to 8.

Another embodiment of the present invention is a method of making anaqueous pharmaceutical composition comprising acetylcysteine, whereinthe pH of the composition is from 6 to 8 and wherein the compositioncontains less than 0.05% chelating agents or is substantially free ofchelating agents, such as EDTA.

Still other embodiments of the present invention are to methods oftreating acetaminophen overdose, liver failure, various cancers,methacrylonitrile poisoning, reduction of radiocontrast-inducednephropathy, reduction of reperfusion injury during cardio bypasssurgery, and diseases where a mucolytic is desired comprisingadministering an aqueous pharmaceutical composition comprisingacetylcysteine, wherein the pH of the composition is from 6 to 8 andwherein the composition contains less than 0.05% chelating agents or issubstantially free of chelating agents, such as EDTA.

Additional objects and advantages of the invention will be set forth inpart in the description which follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

In order that the present invention may be more readily understood,certain terms are first defined. Additional definitions are set forththroughout the detailed description.

The term “stable” or “stability” refers to both the physical andchemical stability of a composition in any form, such as a solution. Acomposition is stable if it exhibits minimal change over time relativeto when it is manufactured. Stability is measured at various time pointsthrough a planned product expiration date with evaluation criteriaincluding such items as therapeutic activity, appearance, levels ofparticulate matter, pH, content of active ingredient(s), and levels ofdegradation products, impurities, or related substances. The stabilityof a composition can be measured as described in Example 3.

As used herein, the term “salt” or “pharmaceutically acceptable salt”refers to acidic salts formed with inorganic and/or organic acids, aswell as basic salts formed with inorganic and/or organic bases. Examplesof these acids and bases are well known to those of ordinary skill inthe art. Salts according to the present invention may be used in avariety of forms. In water and other aqueous solutions, salts typicallydissociate into an “anion,” or negatively charged subcomponent, and a“cation,” or positively charged subcomponent. The salts may also bethose that are physiologically tolerated by a patient, for examplewithout undue toxicity, incompatibility, instability, and allergicresponse.

The term “substantially free” refers to compositions that havesignificantly reduced levels of chelating agents. In one embodiment,chelating agents are not added to the composition, but may be presentotherwise. For instance, the chelating agent may be present as anImpurity or undesired contaminant.

B. Description of the Invention

The Applicant has discovered that liquid compositions of acetylcysteinecan be produced with pharmaceutically acceptable stability in solutionof at least one year at ambient conditions and six months at acceleratedconditions (40° C.) without the need of a chelating agent. Thisstability is surprising given the generally unstable nature ofacetylcysteine.

Chelating agents, or chelators, are organic agents that bond with andthereby sequester free metal ions from solution. A widely used chelatoris edetic acid or ethylenediaminetetraacetic acid, commonly referred toas EDTA. Additional examples of chelating agents include, but are notlimited to, diethylenetriaminepentaacetic acid (DTPA),triethylenetetraaminehexaacetic acid (TTHA),trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA),ethylenediaminedisuccinic acid (EDDS), dihydroxyethyl glycine, citricacid, succinic acid, and tartaric acid A chelator may be used in itsacid form, but it may also be used as one of its salts. Salts of EDTA,for example, include edetate calcium disodium, edetate disodium, edetatesodium, edetate trisodium, and edetate dipotassium.

In one embodiment, the compositions of the invention contain nochelating agents or are substantially free of chelating agents, such asEDTA. In another embodiment the compositions of the invention containless than 0.05% of a chelating agent, such as EDTA. For example, thecomposition of the present invention may contain less than 0.050%,0.045%, 0.040%, 0.035, 0.030%, 0.025%, 0.020%, 0.015%, 0.010%, 0.0050%,0.0025%, 0.0010% of chelating agents, such as EDTA.

Acetylcysteine is the nonproprietary name for the N-acetyl derivative ofthe naturally occurring amino acid, L-cysteine (also known asN-acetyl-L-cysteine and NAG). In one embodiment of the invention, theaqueous compositions of the invention comprise an effective amount ofacetylcysteine. Acetylcysteine includes derivatives of acetylcysteine,and pharmaceutically acceptable salts thereof. Derivatives ofacetylcysteine include, but are not limited to, esters, amides,anhydrides, and thio-esters and thio-ethers of the sulfhydryl moiety.Pharmaceutically acceptable salts of acetylcysteine and acetylcysteinederivatives include, but are not limited to, sodium salts, potassiumsalts, magnesium salts, calcium salts, zinc salts, and ammonium salts.

The amount of acetylcysteine may vary depending on the desiredcharacteristics of the solution and can be determined by one of ordinaryskill in the art. In one embodiment of the invention, the acetylcysteinecomprises 0.1-50%, in another embodiment 1.0-25%, in an additionalembodiment 10%, and in yet another embodiment 20%.

The present inventor has further discovered that a liquid composition ofacetylcysteine can be produced, which is substantially free of orcontains less than 0.05% chelating agents, which has a pH that issuitable for injection or inhalation and can also be used orally. Thus,another embodiment of the invention is a pharmaceutical compositioncomprising an aqueous solution of acetylcysteine, wherein the pH of thecomposition is from 5 to 9. In yet another embodiment of the invention,the pharmaceutical composition comprises an aqueous solution ofacetylcysteine, wherein the pH of the composition is from 6 to 8. Afurther embodiment of the invention is a pharmaceutical compositioncomprising an aqueous solution of acetylcysteine, wherein the pH isabout 6.8, In still other embodiments, the pH of the composition is 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9,8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0.

Formulations of the present invention may further comprise pH-adjustingagents, for example, basic agents. Such agents include a number ofinorganic or organic bases which are pharmaceutically acceptable, in thedosage ranges used, including a monovalent metal alkali and/or adivalent metal alkali, such as, for example, sodium hydroxide solution,potassium hydroxide solution, calcium hydroxide, magnesium hydroxide,ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine,N-methylglucamine, or L-lysine and/or mixtures thereof. In oneembodiment of the invention sodium hydroxide is added to the compositionto adjust the pH of the composition.

The amount of pH-adjusting agent may vary depending on the desired pH ofthe composition and the amount of acetylcysteine in the solution and canbe determined by one of ordinary skill in the art. For example, ingeneral, the amount of a pH-adjusting agent, such as sodium hydroxide,in formulations of the present invention will directly vary depending onthe desired concentration of the acetylcysteine. The exact amount ofpH-adjusting agent to be employed will depend on the particular agentand upon the buffering capacity of the aqueous medium and othercomponents of the formulation employed. Thus, the artisan willappreciate that the optimum amount of pH-adjusting agent will be readilydetermined, for example, by a process of titration to the desired pH.

The present invention also provides for an aqueous pharmaceuticalcomposition consisting of from 10 to 400 mg/mL acetylcysteine and thetitrated amount of sodium hydroxide or other base, dissolved indeaerated water, to achieve the desired pH of the composition, forexample from 6 to 6.

In certain embodiments, the pharmaceutical composition may containformulation materials for modifying, maintaining or preserving, forexample, osmolarity, viscosity, clarity, color, isotonicity, odor,sterility, rate of dissolution or release, adsorption or penetration ofthe composition. In certain embodiments, suitable formulation materialsinclude, but are not limited to, antioxidants (such as ascorbic acid orsodium metabislfuite); bulking/caking agent (such as mannitol, lactose,or trehalose); excipients and/or pharmaceutical adjuvants. (Remington'sPharmaceutical Sciences, 18^(th) Edition, A. R. Gennaro, ed., MackPublishing Company (1990).

The present inventor has further discovered a method of making apharmaceutical composition comprising an aqueous solution ofacetylcysteine and a pH-adjusting agent, wherein the composition issubstantially free of chelating agents or contains less than 0.05%chelating agents. The method comprises the following; addingacetylcysteine to deaerated water, adding a pH-adjusting agent until apH of approximately 6.8 is reached and the acetylcysteine is fullydissolved. Alternatively, acetylcysteine can be added to an aqueousdeaerated solution containing the pH adjusting solution. The resultingproduct is a clear, colorless to light purple solution that can bereadily passed through a sterilizing filter, such as a 0.2 micronfilter. The product is then filled into vials and an inert atmosphere isplaced over the solution prior to sealing. One of ordinary skill in theart will recognize methods of varying the manufacturing process tooptimize the dosage form or increase the product amount for large-scalemanufacturing.

Acetylcysteine administration has been shown to reduce the extent ofliver injury following acetaminophen overdose. The present inventor hasdiscovered a method of treating acetaminophen overdose comprisingadministering to a patient in need thereof an effective amount of apharmaceutical composition comprising an aqueous solution ofacetylcysteine, wherein the composition is substantially free of orcontains less than 0.05% EDTA, or pharmaceutically acceptable saltsthereof. Other conditions alleviated by the aqueous acetylcysteinecompositions of the invention include, but are not limited to, liverfailure, various cancers, methacrylonitrile poisoning, reduction ofradio contrast induced nephropathy, reduction of reperfusion injuryduring cardio bypass surgery, and diseases where a mucolytic is desired.

The pharmaceutical compositions of the invention may be administered byinjection (intravenous or intramuscular), by inhalation, or by the oralroute. In one embodiment of the invention, the composition of theinvention is dissolved in an aqueous solution containing at least one ofdextrose and sodium chloride prior to administration. In anotherembodiment of the invention, the composition of the invention isdissolved in an aqueous solution of 0.45% or 0.90% sodium chloride (halfnormal and normal saline respectively). In yet another composition ofthe invention, it is dissolved in an aqueous solution of 5% dextroseprior to administration. The composition of the invention may also bedissolved in water for injection prior to administration. Other diluentsknown to those of ordinary skill in the art can also be used. Dosages ofthe pharmaceutical composition range from 10 mg per dose to as much as400 mg/kg of acetylcysteine in the pharmaceutical composition and can bedetermined by one of ordinary skill in the art.

In one embodiment the invention, the pharmaceutical composition isadministered to treat acetaminophen toxicity. The composition of theinvention is mixed in 5% dextrose and 150 mg/kg of drug is given over aperiod of 15 minutes to 2 hours as a loading dose immediately followedby a second dose at 50 mg/kg over 4 hours and then by a third dose of100 mg/kg over 20 hours. Additional courses can be given if required.

One of skill in the art will recognize that the appropriate dosage ofthe aqueous acetylcysteine compositions may vary depending on theindividual being treated and the purpose. For example, the age, bodyweight, and medical history of the individual patient may affect theefficacy of the therapy. Further, a lower dosage of the composition maybe needed to treat, for instance, lower weight patients, while heavierpatients require a higher dose of acetylcysteine. A competent physiciancan consider these factors and adjust the dosing regimen to ensure thedose is achieving the desired therapeutic outcome without undueexperimentation. It is also noted that the clinician and/or treatingphysician will know how and when to interrupt, adjust, and/or terminatetherapy in conjunction with individual patient response.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

All numbers expressing percentages of ingredients, components, and soforth used in the specification and claims are to be understood as beingmodified in all instances by the term “w/v.” Accordingly, unlessindicated to the contrary, the percentages set forth in thespecification and attached claims are expressed in weight per unitvolume.

Many modifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only and are not meant to be limiting in anyway. It is intended that the specification and examples be considered asexemplary only, with a true scope and spirit of the invention beingindicated by the claims.

The following examples represent specific embodiments of the foregoingdiscovery, and they are not representative of the entire scope of theinvention. The acetylcysteine, water, sodium hydroxide, and disodiumedentate are Pharmacopoeia grade but other pharmaceutically acceptablematerials can be utilized.

C. Examples

The following examples are offered for illustrative purposes only.

Example 1 Preparation of an Acetylcysteine Formulation

Twenty kilograms of acetylcysteine were added to approximately 60 litersof deaerated water for injection and the solution was mixed. A solutionof sodium hydroxide was added to adjust the pH to approximately 6.5 to7.0 and mixed until dissolved. A sufficient quantity of deaerated waterfor injection was added to make a 20% solution (total volume of 100liters). Exposure to air was minimized by displacing oxygen withnitrogen. The solution was passed through a 0.2 micron sterilizingfilter. The product was filled into vials or ampules and exposure tooxygen minimized by displacing the headspace with nitrogen.

Example 2 Preparation of an Acetylcysteine Formulation

Add 10 kg of acetylcysteine to approximately 60 liters of deaeratedwater for injection and mix. Add a solution of sodium hydroxide toadjust the pH to approximately 6.5 to 7.0 and continue mixing untildissolved. Add a sufficient quantity of deaerated water for injection tomake a 10% solution (total volume of 100 liters). Minimize exposure toair by displacing oxygen with nitrogen or other pharmaceutically inertgas. Pass the solution through a 0.2 micron or other sterilizing filter.Fill the product into vials or ampules minimizing exposure to oxygen bydisplacing the headspace with nitrogen or other pharmaceutically inertgas.

Example 3 Stability of Acetylcysteine Compositions of the Invention

To determine whether the stability of acetylcysteine solutions requiredEDTA, three solutions containing different concentrations of edetatedisodium were manufactured. The stability of a solution containing 0.05%edetate disodium, a solution containing 40% of that amount, 0.02%edetate disodium, and a solution containing no edetate disodium (0.00%)was examined. The three solutions were manufactured using similarprocesses to the process described in Example 1. Briefly, the edetatedisodium, if any, was added in approximately 60% of the requireddeaerated water and mixed until dissolved. Acetyloysteine was then addedand mixed until dissolved. The pH was adjusted to approximately 6.8 withsodium hydroxide and deaerated water was added to the target level.Nitrogen was used to purge the solutions. The product was then passedthrough a 0.2 micron filter to remove potential microbial contaminationand was filled into vials.

At an initial time point, high performance liquid chromatography (HPLC)was used to assess the acetylcysteine content and chromatographic purityof the three solutions. Measurements were taken of various impuritiesincluding, L-cysteine, impurity C, (disulfide), impurity D, and otherimpurities or degradation products. The peak areas for these HPLCmeasurements are presented in Table 1. An analysis of unknown peaks inthe chromatograms was also undertaken. The “highest unknown” representsthe area of the highest individual unidentified peak in thechromatogram, while “total unknowns” represents the total area ofunidentified peaks in the chromatogram. See Table 1. In addition toHPLC, the visual appearance, pH, and levels of particulates of each ofthe three solutions were examined. Vials containing the three solutionswere then placed at either 25° C. or 40° C. and vials were removed 43months, 6 months, and 12 months and assayed for the parameters describedabove. See Table 1.

Appearance, pH, and particulate matter remained constant over timebetween the three formulations. As shown in Table 1, there were nosignificant differences between each of the three solutions inacetylcysteine content or purity. The results demonstrate that edetateis not required to produce a product with pharmaceutically acceptablestability. These results are surprising given the generally unstablenature of acetylcysteine.

TABLE 1 Acetyl- Disodium cysteine L- Impurity C Impurity Highest TotalTime-point EDTA Temp Content Cysteine (Disulfide) D Unknown UnknownsInitial 0.00% N/A 202.4 0.15 0.55 0.18 0.01 0.02 Initial 0.02% N/A 203.90.19 0.44 0.23 0.03 0.05 Initial 0.05% N/A 204.7 0.20 0.50 0.30 0.040.10 3 Months 0.00% 25° C. 204.2 0.181 0.482 0.137 0.053 0.080 3 Months0.00% 40° C. 201.8 0.370 0.540 0.90 0.070 0.132 3 Months 0.02% 25° C.204.9 0.259 0.436 0.191 0.074 0.141 3 Months 0.02% 40° C. 204.5 0.4630.467 0.142 0.065 0.183 3 Months 0.05% 25° C. 206.1 0.299 0.444 0.2140.044 0.119 3 Months 0.05% 40° C. 205.4 0.532 0.507 0.165 0.045 0.154 6Months 0.00% 25° C. 202.4 0.262 0.523 0.106 0.013 0.013 6 Months 0.00%40° C. 201.7 0.707 0.509 0.053 0.133 0.133 6 Months 0.02% 25° C. 205.90.338 0.391 0.167 0.013 0.013 6 Months 0.05% 25° C. 207.1 0.369 0.4830.186 0.013 0.013 6 Months 0.05% 40° C. 204.6 0.932 0.509 0.104 0.1350.135 6 Months 0.02% 40° C. 204.3 0.856 0.525 0.093 0.135 0.135 12Months  0.00% 25° C. 204.5 0.364 0.597 0.079 0.034 0.071 12 Months 0.02% 25° C. 206.0 0.435 0.475 0.134 0.042 0.130 12 Months  0.05% 25° C.207.1 0.514 0.435 0.160 0.055 0.122

1. An aqueous pharmaceutical composition comprising acetylcysteine,wherein the composition is substantially free of EDTA orpharmaceutically acceptable salts thereof.
 2. An aqueous pharmaceuticalcomposition comprising acetylcysteine, wherein the composition containsless than 0.05% w/v EDTA, or pharmaceutically acceptable salts thereof.3. The aqueous pharmaceutical composition of claim 2, wherein thecomposition contains less than 0.02% w/v EDTA, or pharmaceuticallyacceptable salts thereof.
 4. The aqueous pharmaceutical composition ofclaim 3, wherein the composition contains no EDTA, or pharmaceuticallyacceptable salts thereof.
 5. The aqueous pharmaceutical composition ofclaim or 2, wherein the pH of the composition is from 6 to
 8. 6. Theaqueous pharmaceutical composition of claim 5, wherein the pH of thecomposition is from 6.5 to 7.0.
 7. The aqueous pharmaceuticalcomposition of claim 6, wherein the pH of the composition is 6.8.
 8. Theaqueous pharmaceutical composition of claim 1, wherein the compositionis stable for at least 12 months at 25° C.
 9. The aqueous pharmaceuticalcomposition of claim 1, wherein the composition is stable for at least 6months at 40° C.
 10. An aqueous pharmaceutical composition consisting offrom 10 to 400 mg/mL acetylcysteine, dissolved in deaerated water, andwherein the pH of the composition is adjusted with a pH-adjusting agentto a pH of from 6 to
 8. 11. A method of treating acetaminophen overdose,comprising administering to a patient in need thereof an effectiveamount of an aqueous composition of acetylcysteine, wherein saidcomposition is substantially free of EDTA or pharmaceutically acceptablesalts thereof.
 12. A method of treating acetaminophen overdose,comprising administering to a patient in need thereof an effectiveamount of an aqueous composition of acetylcysteine, wherein saidcomposition contains less than 0.05% w/v EDTA or pharmaceuticallyacceptable salts thereof.
 13. The method of claim 12, wherein thecomposition contains less than 0.02% w/v EDTA, or pharmaceuticallyacceptable salts thereof.
 14. The method of claim 13, wherein thecomposition contains no EDTA, or pharmaceutically acceptable saltsthereof.
 15. The method of claim 11, wherein the pH of the compositionis from 6 to
 8. 16. The method of claim 15, wherein the pH of thecomposition is from 6.5 to 7.0.
 17. The method of claim 16, wherein thepH of the composition is 6.8.
 18. The method of claim 11, wherein theadministration occurs via intravenous injection, orally, or byinhalation.
 19. The method of claim 18 wherein the method ofadministration occurs via intravenous injection.
 20. The method of claim11, wherein the composition is mixed in an aqueous solution of at leastone of dextrose and sodium chloride prior to administration.
 21. Themethod of claim 20, wherein the composition is mixed in an aqueoussolution of 5% w/v dextrose prior to administration.
 22. The method ofclaim 20, wherein the composition is mixed in an aqueous solution of0.45% or 0.90% w/v sodium chloride prior to administration.
 23. A methodof making an aqueous acetylcysteine pharmaceutical composition,comprising dissolving acetylcysteine in deaerated water and adding abasic agent to achieve a pH of 6 to 8, wherein the composition issubstantially tree of EDTA or pharmaceutically acceptable salts thereof.24. A method of making an aqueous acetylcysteine pharmaceuticalcomposition, comprising dissolving acetylcysteine in deaerated water andadding a basic agent to achieve a pH of 6 to 8, wherein the compositioncontains less than 0.05% w/v EDTA, or pharmaceutically acceptable saltsthereof.
 25. The method of claim 23, wherein the method furthercomprises passing the solution through a sterilizing filter and fillingunder an inert atmosphere.
 26. The method of claim 24, wherein thecomposition contains less than 0.02% w/v EDTA, or pharmaceuticallyacceptable salts thereof.
 27. The method of claim 26, wherein thecomposition contains no EDTA, or pharmaceutically acceptable saltsthereof.
 28. The method of claim 23, wherein the pH of the compositionis from 6.5 to 7.0.
 29. The method of claim 28, wherein the pH of thecomposition is 6.8.
 30. The method of claim 23, wherein the compositionis stable for at least 6 months at 25° C.
 31. The method of claim 23,wherein the composition is stable for at least 6 months at 40° C. 32.The method of claim 23, wherein the basic agent is sodium hydroxide. 33.A method of treating liver failure, comprising: using a stable aqueouspharmaceutical composition comprising from 10 to 250 mg/mLacetylcysteine or pharmaceutically acceptable salts thereof, wherein thecomposition contains less than 0.05% w/v chelating agents, wherein saidcomposition is in a suitable form for intravenous administration;diluting the composition in an aqueous solution; and administering thediluted composition to a patient in need thereof.
 34. The method ofclaim 33, wherein the pH of the composition in an undiluted state isfrom 5 to
 9. 35. The method of claim 33, wherein the pH of thecomposition in an undiluted state is from 6.0 to 7.5.
 36. The method ofclaim 33, wherein the composition in an undiluted state comprises from100 to 250 mg/mL acetylcysteine or pharmaceutically acceptable saltsthereof.
 37. The method of claim 33, wherein the composition in anundiluted state comprises about 200 mg/mL acetylcysteine orpharmaceutically acceptable salts thereof.
 38. The method of claim 33,wherein the diluted composition is administered as a loading dose ofabout 150 mg/kg, followed by a second dose of about 50 mg/kg.
 39. Themethod of claim 33, wherein the diluted composition is administered as aloading dose over a period of 15 minutes to 2 hours, followed by asecond dose over about 4 hours.
 40. The method of claim 33, wherein theaqueous solution comprises at least one of 5% dextrose, 0.45% sodiumchloride, and water for injection.
 41. The method of claim 33, whereinthe composition contains less than 0.02% chelating agents.
 42. Themethod of claim 33, wherein the liver failure is acute liver failure.43. The method of claim 33, wherein said composition is sealed in anairtight container comprising a fill volume of said composition and aheadspace volume occupied by a pharmaceutically inert gas.
 44. Themethod of claim 33, wherein chelating agents are not added to thecomposition but may be present as an impurity or undesired contaminant.45. The method of claim 33, wherein the composition is free of chelatingagents.